Cognitive ability may decline as a normal consequence of aging. Moreover, a significant population of elderly adults experiences a decline in cognitive ability that exceeds what is typical in normal aging. Mild Cognitive Impairment (MCI) reflects a degree of cognitive impairment without dementia that does not interfere with the activities of daily living. It is thought to be a prodromal state for Alzheimer's disease (De Carli, 2003; Petersen et al., 2009; Petersen et al., 1999). The prevalence of MCI is between 14% and 18% in those over 70 years old (Petersen et al., 2009; Plassman et al., 2008), which means that about 5 million people in the USA and 14 million in greater Europe suffer from this condition. Approximately half of those with MCI convert to Alzheimer's disease or to another form of dementia within 5 years (DeCarli, 2003) and thus there is an urgent need to identify treatments that will slow down or prevent this conversion. So far, no trial has been successful and currently there is no approved treatment for MCI.
In cognitively healthy elderly, the brain shows significant progressive atrophy (Resnick et al., 2003) and a much increased rate of brain atrophy is associated with the conversion from normal ageing to Alzheimer's disease (Bradley et al., 2002; Fox et al., 1999; Jack et al., 2004; Smith, 2002). An intermediate rate of atrophy is found in MCI (Carlson et al., 2008; Jack et al., 2005; Killiany et al., 2000; Ries et al., 2008; Risacher et al., 2009; Sluimer et al., 2008). Since the rate of brain atrophy is more rapid in subjects with MCI who convert to Alzheimer's disease (Jack et al., 2004), it is important to identify factors that determine the rate of atrophy since reducing the rate of atrophy might slow the conversion to Alzheimer's disease. One such factor appears to be raised concentrations of plasma total homocysteine (tHcy). Moderately elevated concentrations of tHcy have been associated with an increased risk of dementia, notably Alzheimer's disease, in many cross-sectional and prospective studies (Clarke et al., 1998; McCaddon et al., 1998; Seshadri, 2006; Smith, 2008; Zylberstein et al., 2009). Raised tHcy is also associated with both regional and whole brain atrophy, not only in Alzheimer's disease (Clarke et al., 1998) but also in normal elderly (den Jeijer et al., 2003a; Sachdev et al., 2002; Seshadri et al., 2008; Williams et al., 2002; Yang et al., 2007). Thus, there remains a requirement to identify new treatments for the treatment of MCI that may act to retard brain atrophy in a subject and lowering tHcy levels could be one possible approach.
Despite the reported link between MCI and Alzheimer's Disease, it has been shown that it does not necessarily follow that treatments authorised for the treatment of Alzheimer's Disease have an effect on MCI patients. For example, clinical trials have been carried out on whether the Alzheimer's drug, galantamine, can be used as a treatment of MCI. These trials did not find any significant benefit for galantamine in improving function or preventing transition to Alzheimer's. However, investigators did note a significantly greater number of deaths in the galantamine treatment groups than in those receiving the placebo. (Winblad B, Gauthier S, Scinto L, Feldman H, Wilcock G K, et al. (2008) Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 70: 2024-2035.)
Clinical trials have also been carried out to determine whether rivastigmine (Exelon®) delayed the transition from MCI to Alzheimer's Disease. The trials found no significant benefit of rivastigmine on the progression rate to Alzheimer's Disease nor on cognitive function over four years. (Feldman H H, Ferris S, Winblad B, Sfikas N, Mancione L, et al. (2007) Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol 6: 501-512.)
Thus, clinical trials have indicated that medicaments authorised for Alzheimer's Disease do not necessarily have any therapeutic effect on MCI or a conversion between MCI and Alzheimer's Disease.